Factores de crecimiento aportados por el lisado plaquetario en el tratamiento tópico de úlceras posflebíticas / Platelet lysate-derived growth factors for topical treatment of postphlebitis ulcers

Introducción: los factores de crecimiento plaquetario son proteínas bioactivas que se sintetizan y almacenan en las plaquetas. Objetivo: evaluar la efectividad de los factores de crecimiento aportados por el lisado plaquetario alogénico en el tratamiento tópico de úlceras posflebíticas Métodos: se realizó un estudio cuasi-experimental con control simultáneo en la consulta de medicina regenerativa, Hospital General Docente "Comandante Pinares", entre enero de 2008 y diciembre de 2012. Se evaluaron 135 pacientes con el diagnóstico de úlceras posflebíticas con inadecuada respuesta al tratamiento convencional y ausencia de otras enfermedades de base que impidieran una respuesta a la terapia regenerativa. Los pacientes se dividieron en dos grupos: 90 recibieron tratamiento con la aplicación local del lisado plaquetario obtenido de las plaquetas alogénicas ABO compatibles y 45 mantuvieron el tratamiento convencional (grupo control). El tiempo de respuesta fue la característica distintiva para medir la eficacia entre ambos tratamientos. Resultados: predominó el sexo femenino y edad de más de 50 años. Los síntomas cardinales del síndrome posflebítico, estuvieron presentes en un mayor número de pacientes del grupo tratado con el lisado plaquetario, sin embargo, a los 30 días, se constató una mejoría de los mismos así como una disminución significativa del área promedio de las úlceras. En el grupo tratado con lisado, 86 pacientes remitieron sus síntomas en menos de seis semanas, frente a solo ocho en el mismo tiempo en el grupo convencional. Conclusiones: el uso de factores de crecimiento aportados por el lisado plaquetario alogénico fue efectivo en el tratamiento tópico de úlceras posflebíticas(AU)

Introduction: platelet-derived growth factors are bio-active proteins that are synthesized and stored in the platelets. Objective: to evaluate the effectiveness of allogenic platelet lysate-derived growth factors in the topical treatment of postphlebitis ulcers. Methods: a quasi-experimental study with simultaneous control was conducted from January 2008 through December 2012 in the regenerative medicine service of "Comandante Pinares" general teaching hospital located in San Cristobal, Artemisa province, Cuba. One hundred and thirty five patients with diagnosis of postphlebitis ulcers, inadequate response to the conventional treatment and absence of other illnesses that could hinder such response to regenerative therapy were evaluated. The patients were divided into two groups: 90 treated with local use of compatible ABO allogenic platelet-derived platelet lysate and 45 kept under the conventional treatment (control group). The reaction time was the distinctive characteristic to measure the effectiveness of both treatments. Results: females and over 50 years-old age predominated. The main symptoms of the posphlebitic syndrome were present in a high number of patients in the group treated with the platelet lysate. Thirty days later, these symptoms significantly improved and the average ulcer area dramatically decreased. There was observed symptoms remission in eighty six patients in less than six weeks in contrast with only eight in the conventional group during this period. Conclusions: the use of allogenic platelet lysate-derived growth factors was effective in the topical treatment of postphlebitis ulcers(AU)

Aplicación local de lisado plaquetario en úlceras posflebíticas / Local application of platelet lysate on posflebitic ulcers

El tratamiento de las úlceras postrombóticas o posflebíticas constituye un reto para la medicina debido a su cronicidad y a sus frecuentes recidivas que condicionan múltiples trastornos locales y sistémicos, con una mala calidad de vida del paciente. En este trabajo se incluyeron 80 pacientes con úlceras posflebíticas en miembros inferiores que fueron divididos en 2 grupos: 40 tratados con lisados de plaquetas alogénicas conservadas y 40 tratados convencionalmente, que conformaron el grupo control. Se consideró como buen resultado cuando a los 30 días de tratamiento o antes, el paciente presentó una respuesta parcial o total. En el 95 por ciento de los enfermos tratados con el lisado se obtuvo una buena respuesta (suma de las totales y parciales) contra el 75 por ciento en el grupo control (p>0,001). El uso del lisado plaquetario resultó un proceder simple y efectivo en el tratamiento de úlceras posflebíticas en miembros inferiores, que puede ser recomendado, ya que los pacientes pueden mantenerse en sus hogares y así se elimina el costo hospitalario que generalmente tiene el tratamiento de este tipo de lesión

Treatment of post-thrombotic ulcers or postflebitic is a challenge to medicine because of its chronicity and frequent recurrences that determine multiple local and systemic disorders with poor quality of life for patients. This study included 80 patients with lower limb posflebitic ulcers, who were grouped into 2 groups: 40 treated with preserved allogeneic platelet lysates and 40 were treated conventionally. The latter was the control group. It was considered good result when the patient had a partial or complete response after 30 days of treatment or before. Good response was found in 95 percent of patients treated with lysate (sum of total and partial values) versus 75 percent in the control group (p> 0.001). The use of platelet lysate was a simple and effective procedure in the treatment of lower limb posflebitic ulcers. This treatment can be recommended, since patients can stay at home, thus eliminating the hospital costs incurred in this type of treatment

Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice.

Recent GWAS have identified SNPs at a human chromosom1 locus associated with coronary artery disease risk and LDL cholesterol levels. The SNPs are also associated with altered expression of hepatic sortilin-1 (SORT1), which encodes a protein thought to be involved in apoB trafficking and degradation. Here, we investigated the regulation of Sort1 expression in mouse models of obesity. Sort1 expression was markedly repressed in both genetic (ob/ob) and high-fat diet models of obesity; restoration of hepatic sortilin-1 levels resulted in reduced triglyceride and apoB secretion. Mouse models of obesity also exhibit increased hepatic activity of mammalian target of rapamycin complex 1 (mTORC1) and ER stress, and we found that administration of the mTOR inhibitor rapamycin to ob/ob mice reduced ER stress and increased hepatic sortilin-1 levels. Conversely, genetically increased hepatic mTORC1 activity was associated with repressed Sort1 and increased apoB secretion. Treating WT mice with the ER stressor tunicamycin led to marked repression of hepatic sortilin-1 expression, while administration of the chemical chaperone PBA to ob/ob mice led to amelioration of ER stress, increased sortilin-1 expression, and reduced apoB and triglyceride secretion. Moreover, the ER stress target Atf3 acted at the SORT1 promoter region as a transcriptional repressor, whereas knockdown of Atf3 mRNA in ob/ob mice led to increased hepatic sortilin-1 levels and decreased apoB and triglyceride secretion. Thus, in mouse models of obesity, induction of mTORC1 and ER stress led to repression of hepatic Sort1 and increased VLDL secretion via Atf3. This pathway may contribute to dyslipidemia in metabolic disease.

Homozygous disruption of Pctp modulates atherosclerosis in apolipoprotein E-deficient mice.

Phosphatidylcholine transfer protein (PC-TP) is a cytosolic phospholipid binding protein and a member of the steroidogenic acute regulatory-related transfer domain superfamily. Its tissue distribution includes liver and macrophages. PC-TP regulates hepatic lipid metabolism, and its absence in cholesterol-loaded macrophages is associated with reduced ATP binding cassette transporter A1-mediated lipid efflux and increased susceptibility to apoptosis induced by unesterified cholesterol. To explore a role for PC-TP in atherosclerosis, we prepared PC-TP-deficient/apolipoprotein E-deficient (Pctp(-/-)/Apoe(-/-)) mice and littermate Apoe(-/-) controls. At 16 weeks, atherosclerosis was increased in chow-fed male, but not female, Pctp(-/-)/Apoe(-/-) mice. This effect was associated with increases in plasma lipid concentrations. By contrast, no differences in atherosclerosis were observed between male or female Pctp(-/-)/Apoe(-/-) mice and Apoe(-/-) controls fed a Western-type diet for 16 weeks. At 24 weeks, atherosclerosis in chow-fed male Pctp(-/-)/Apoe(-/-) mice tended to be reduced in proportion to plasma cholesterol. The attenuation of atherosclerosis in female Pctp(-/-)/Apoe(-/-) mice fed chow or the Western-type diet for 24 weeks was not attributable to changes in plasma cholesterol or triglyceride concentrations. These findings suggest that PC-TP modulates the development of atherosclerosis, in part by regulating plasma lipid concentrations.

Decreased lipid efflux and increased susceptibility to cholesterol-induced apoptosis in macrophages lacking phosphatidylcholine transfer protein.

Macrophages are the predominant cellular component of atherosclerotic lesions, where they scavenge oxidatively modified lipoproteins while defending themselves against cholesterol-induced cytotoxicity by adaptive mechanisms that depend in part on the synthesis, distribution and efflux of phosphatidylcholines. PC-TP (phosphatidylcholine transfer protein) is a START (steroidogenic acute regulatory protein-related lipid transfer) domain protein that catalyses the intermembrane transfer of phosphatidylcholines and promotes apolipoprotein AI-mediated lipid efflux when overexpressed in the cytosol of Chinese-hamster ovary cells. To explore a role for PC-TP in the adaptive responses of macrophages to cholesterol loading, we utilized peritoneal macrophages from mice with homozygous disruption of the gene encoding PC-TP (Pctp(-/-)) and wild-type littermate controls. PC-TP was abundantly expressed in macrophages from wild-type but not Pctp(-/-) mice. In cholesteryl ester-loaded macrophages from Pctp(-/-) mice, the apolipoprotein AI-mediated efflux of phospholipids and cholesterol was decreased. This could be attributed to proportional decreases in the expression levels of ATP-binding cassette A1. Also, in response to free cholesterol loading, the absence of PC-TP from macrophages was associated with marked increases in apoptotic cell death. These findings suggest that PC-TP in macrophages may serve an atheroprotective role by defending against cholesterol-induced cytotoxicity.

Phosphatidylcholine transfer protein promotes apolipoprotein A-I-mediated lipid efflux in Chinese hamster ovary cells.

Phosphatidylcholine transfer protein (PC-TP) is a cytosolic protein of unknown function that catalyzes intermembrane transfer of phosphatidylcholines in vitro. Using stably transfected CHO cells, we explored the influence of PC-TP on apolipoprotein A-I- and high density lipoprotein 3 (HDL(3))-mediated lipid efflux. In proportion to its cellular level of expression, PC-TP accelerated apolipoprotein A-I-mediated phospholipid and cholesterol efflux as pre-beta-HDL particles. PC-TP increased rates of efflux of both lipids by >2-fold but did not affect mRNA levels or the activity of ATP-binding cassette A1, a plasma membrane protein that regulates apolipoprotein A-I-mediated lipid efflux. Overexpression of PC-TP was associated with only slight increases in HDL(3)-mediated phospholipid efflux and no changes in cholesterol efflux. In scavenger receptor BI-overexpressing cells, PC-TP expression minimally influenced apolipoprotein A-I- or HDL(3)-mediated lipid efflux. PC-TP did not affect cellular phospholipid compositions, phosphatidylcholine contents, or phosphatidylcholine synthetic rates. These findings suggest that a physiological function of PC-TP is to replenish the plasma membrane with phosphatidylcholines that are removed during pre-beta-HDL particle formation due to the activity of ATP-binding cassette A1.